High-Voltage Power Supply for Four-Quadrant Dielectric Elastomer Actuators.

Dielectric elastomer actuators (DEAs) are emerging as promising candidates for various applications in robotics and optical devices due to their lightweight, miniaturization potential, high energy density, simple structure, and low power consumption. However, their effective actuation always demands sophisticated high-voltage driving circuits that are compact and responsive. DEAs need to be capable of generating intricate high-voltage waveforms or simultaneously controlling multiple quadrants with distinct high-voltage levels. This paper proposes a high-voltage power supply for DEAs, featuring a four-quadrant high-voltage driving circuit. The circuit is capable of independently generating high-voltage signals ranging from 100 V to 6000 V and producing arbitrary waveforms with adjustable frequencies. The independent operation of the quadrants without crosstalk showcases the system's integration and potential for cross-disciplinary applications.

Search for Cosmic-Ray Boosted Sub-MeV Dark-Matter-Electron Scattering in PandaX-4T.

We report the first search for the elastic scatterings between cosmic-ray boosted sub-MeV dark matter (DM) and electrons in the PandaX-4T liquid xenon experiment. Sub-MeV DM particles can be accelerated by scattering with electrons in the cosmic rays and produce detectable electron recoil signals in the detector. Using the commissioning data from PandaX-4T of 0.63 tonne·year exposure, we set new constraints on DM-electron scattering cross sections for DM masses ranging from 10 eV/c^{2} to 3 keV/c^{2}.

Odor identification dysfunction in late-life depression with suicidal ideation.

BACKGROUND: Suicide is more prevalent among older adults compared to younger individuals. Late-life depression (LLD) poses the highest risk for suicide. However, early recognition of suicidal ideation is challenging. Dysfunction in odor identification (OI), a characteristic of LLD, may hold potential for early identification of suicidal ideation. This study aims to compare OI between LLD patients with suicidal ideation (LLD-S) and LLD patients without suicidal ideation (LLD-NS), and examine its relationship with cognitive function. METHODS: A total of 262 LLD-NS patients, 63 LLD-S patients, and 316 healthy normal older adults (HOAs) underwent OI testing, standardized clinical interviews, and comprehensive neuropsychological assessments. RESULTS: (1) LLD-S patients exhibited lower OI scores and poorer cognitive performance (including global cognition, information processing speed, memory, language, executive function, and visuospatial ability) compared to LLD-NS patients and HOAs. (2) There were interactive effects between suicidal ideation and OI dysfunction, leading to lower scores in information processing speed and visuospatial ability. (3) OI dysfunction mediated the differences in cognition between the LLD-NS and LLD-S groups. LIMITATIONS: The present study was a cross-sectional design. CONCLUSIONS: LLD-S patients had worse odor identification than LLD-NS patients and HOAs, suggesting that OI testing could be a valuable approach for identifying suicidal ideation in LLD and screening for suicide risk. The presence of both OI impairment and suicidal ideation was associated with poorer cognitive performance in LLD.

Revealing the impact of sample enrichment method on concentration and cytotoxicity of volatile disinfection byproducts in drinking water: A quantitative study for liquid-liquid extraction.

Liquid-liquid extraction (LLE) combined with the N2 blow-down method is a promising tool for bioanalysis of drinking water. However, detailed information on which disinfection byproduct (DBP) classes are retained in LLE extracts is currently unavailable. In this study, the recovery of seven classes of volatile DBPs and total adsorbable organic halogens (TOX) during the LLE method, combined with three common N2 blow-down methods, for bioanalysis in real tap water was analyzed at a 2-L scale, along with their corresponding cytotoxicity. The total concentration of seven classes of volatile DBPs in drinking water in Suzhou ranged from 64.6 to 83.0 µg/L, with the majority contributed by trihalomethanes (THMs: 59.9 µg/L), haloaldehydes (HALs: 5.4 µg/L), haloacetamides (HAMs: 3.4 µg/L), and haloacetonitriles (HANs: 3.2 µg/L). During the LLE - N2 blow-down process for bioanalysis, about 69-85 % of targeted volatile DBPs and 64-75 % of TOX were lost, respectively. Seven classes of volatile DBPs accounted for 52.8-64.3 % and 23.8-61.3 % of TOX in tap water and LLE - N2 blow-down samples, respectively, suggesting that targeted aliphatic DBPs are the key contributors to TOX. Furthermore, although LLE - solvent exchange had a better recovery performance than other N2 blow-down methods, the recoveries of volatile DBPs using this method were still not ideal. For example, HALs and HAMs had a slightly better recovery (>50 %), while most volatile DBPs had a poor recovery, including iodo-trihalomethanes (I-THMs, 0 %), haloketones (28 %), THMs (26 %), halonitromethanes (33 %), and HANs (38 %). During LLE - solvent exchange, 31 % and 36 % of targeted DBPs and TOX, respectively, in real tap water can be retained, which shows better performance than non-ionic macroporous copolymers (XAD). More importantly, the water volume required in this method for cytotoxicity analysis is 2 L, which greatly reduces the burden of water sample collection, transport, and pre-treatment compared to XAD (which typically requires 5 or 10 L). In general, this paper reveals the fate of volatile DBPs during LLE - N2 blow-down and indicates that LLE - solvent exchange is a good substitute for the XAD method in bioanalysis.

Chemosensory anhedonia facilitates depressive symptoms and cognitive impairment in late-life depression.

AIM: Chemosensory anhedonia refers to the lack of hedonic ability to experience pleasure through the senses of smell and taste, which reduces the pleasure and comfort of food, and increases the risk of nutritional and immune deficiencies. However, there is no direct scientific evidence regarding chemosensory anhedonia in patients with late-life depression (LLD). The aim of this study was to investigate chemosensory anhedonia in patients with LLD, and its potential association with depressive symptoms and cognitive function. METHODS: A total of 114 patients with LLD and 92 normal controls were included in this study. They experienced clinical assessment, Chemosensory Pleasure Scale assessment, 17-item Hamilton Depression Rating Scale assessment and cognitive assessments, which contain the Verbal Fluency Test. The associations between chemosensory pleasure and depressive symptoms or cognitive function in patients with LLD were explored using partial correlation analysis and mediation analysis. RESULTS: The Chemosensory Pleasure Scale scores were lower in the LLD group than in the normal control group, and were negatively correlated with the total scores and factors' scores (retardation, cognitive bias and anxiety/somatization) of the 17-item Hamilton Depression Rating Scale, and positively correlated with the Verbal Fluency Test scores. The scores for the Food and Imagination dimensions of the Chemosensory Pleasure Scale showed partial mediating effects on the differences in Cognitive bias (a factor of the 17-item Hamilton Depression Rating Scale) between patients with LLD and normal controls. CONCLUSIONS: Patients with LLD showed significant chemosensory anhedonia, and both depressive symptoms and cognitive impairment were associated with the severity of chemosensory anhedonia. Enhancing chemosensory pleasure in patients with LLD could potentially ameliorate their depressive symptoms. Geriatr Gerontol Int 2024; ••: ••-••.

Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP.

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl4) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.

Flavonoids: Potential therapeutic agents for cardiovascular disease.

Flavonoids are found in the roots, stems, leaves, and fruits of many plant taxa. They are related to plant growth and development, pigment formation, and protection against environmental stress. Flavonoids function as antioxidants and exert anti-inflammatory effects in the cardiovascular system by modulating classical inflammatory response pathways, such as the TLR4-NF-ĸB, PI3K-AKT, and Nrf2/HO-1 signalling pathways. There is increasing evidence for the therapeutic effects of flavonoids on hypertension, atherosclerosis, and other diseases. The potential clinical value of flavonoids for diseases of the cardiovascular system has been widely explored. For example, studies have evaluated the roles of flavonoids in the regulation of blood pressure via endothelium-dependent and non-endothelium-dependent pathways and in the regulation of myocardial systolic and diastolic functions by influencing calcium homeostasis and smooth muscle-related protein expression. Flavonoids also have hypoglycaemic, hypolipidemic, anti-platelet, autophagy, and antibacterial effects. In this paper, the role and mechanism of flavonoids in cardiovascular diseases were reviewed in order to provide reference for the clinical application of flavonoids in the future.

Olfactory Dysfunction as a Marker for Cognitive Impairment in General Paresis of the Insane: A Clinical Study.

BACKGROUND General paresis of the insane (GPI) is characterized by cognitive impairment, neuropsychiatric symptoms, and brain structural abnormalities, mimicking many neuropsychiatric diseases. Olfactory dysfunction has been linked to cognitive decline and neuropsychiatric symptoms in numerous neuropsychiatric diseases. Nevertheless, it remains unclear whether patients with GPI experience olfactory dysfunction and whether olfactory dysfunction is associated with their clinical manifestations. MATERIAL AND METHODS Forty patients with GPI and 37 healthy controls (HCs) underwent the "Sniffin Sticks" test battery, Mini-Mental State Examination, and Neuropsychiatric Inventory to measure olfactory function, cognitive function, and neuropsychiatric symptoms, respectively. Brain structural abnormalities were evaluated using visual assessment scales including the medial temporal lobe atrophy (MTA) visual rating scale and Fazekas scale. RESULTS Compared with HCs, patients with GPI exhibited significant olfactory dysfunction, as indicated by deficits in the odor threshold (OT) (P=0.001), odor discrimination (OD) (P<0.001), and odor identification (OI) (P<0.001). In patients with GPI, the OI was positively correlated with cognitive function (r=0.57, P<0.001), but no significant correlation was found between olfactory function and neuropsychiatric symptoms, blood, or cerebrospinal fluid biomarkers (rapid plasma reagin circle card test and Treponema pallidum particle agglutination test), or brain structural abnormalities (MTA and Fazekas scale scores). Mediation analysis indicated that the impaired OI in patients with GPI was mediated by cognitive impairment and impaired OT respectively. CONCLUSIONS Patients with GPI exhibited overall olfactory dysfunction. OI is correlated with cognitive function and the impaired OI is mediated by cognitive impairment in patients with GPI. Thus, OI may serve as a marker for reflecting cognitive function in patients with GPI.

Abnormalities in Electroencephalographic Microstates in Patients with Late-Life Depression.

Background: Late-life depression (LLD) is characterized by disrupted brain networks. Resting-state networks in the brain are composed of both stable and transient topological structures known as microstates, which reflect the dynamics of the neural activities. However, the specific pattern of EEG microstate in LLD remains unclear. Methods: Resting-state EEG were recorded for 31 patients with episodic LLD (eLLD), 20 patients with remitted LLD (rLLD) and 32 healthy controls (HCs) using a 64-channel cap. The clinical data of the patients were collected and the 17-Item Hamilton Rating Scale for Depression (HAMD) was used for symptom assessment. Duration, occurrence, time coverage and syntax of the four microstate classes (A-D) were calculated. Group differences in EEG microstates and the relationship between microstates parameters and clinical features were analyzed. Results: Compared with NC and patients with rLLD, patients with eLLD showed increased duration and time coverage of microstate class D. Besides, a decrease in occurrence of microstate C and transition probability between microstate B and C was observed. In addition, the time coverage of microstate D was positively correlated with the total score of HAMD, core symptoms, and miscellaneous items. Conclusion: These findings suggest that disrupted EEG microstates may be associated with the pathophysiology of LLD and may serve as potential state markers for the monitoring of the disease.

Haloketones: A class of unregulated priority DBPs with high contribution to drinking water cytotoxicity.

Although unregulated aliphatic disinfection byproducts (DBPs) had a much higher concentration and cytotoxicity than known aromatic DBPs, a recent study indicated that seven classes of regulated and unregulated priority DBPs (one and two-carbon-atom DBPs) just accounted for 16.2% of disinfected water cytotoxicity in the U.S., meaning some of the highly toxic aliphatic DBPs may be overlooked. Haloketones (HKs) are an essential class of priority DBPs with a 1-100 µg/L concentration in drinking water but lack cytotoxicity data. This study investigated the cytotoxicity of seven HKs using Chinese hamster ovary (CHO) cells. The order for cytotoxicity of HKs from most to least toxic was: 1,3-dichloroacetone (LC50: 1.0 ± 0.20 µM) ≈ 1,3-dibromoacetone (1.5 ± 0.19 µM) ≈ bromoacetone (1.9 ± 0.49 µM) > chloroacetone (4.3 ± 0.22 µM) > 1,1,3-trichloropropanone (6.6 ± 0.46 µM) > 1,1,1-trichloroacetone (222 ± 7.7 µM) > hexachloroacetone (3269 ± 344 µM). The cytotoxicity of HKs was higher than most regulated and priority aliphatic DBPs in mono-halogenated, di-halogenated, and tri-halogenated categories. A prediction model of HK cytotoxicity was developed based on the quantitative structure-activity relationship (QSAR), optimizing structures and computing descriptors with Gaussian 09 W. The average concentrations of HKs in representative drinking water samples from South Carolina (U.S.) and Suzhou (China) were 12.4 and 0.9 µg/L, respectively, accounting for 18.8% and 1.7% of their specific total DBPs measured (i.e. not TOX). For South Carolina drinking water, their contributions to total calculated additive cytotoxicity of aliphatic DBPs and overall drinking water cytotoxicity were 86.7% and 14.0%, respectively, demonstrating that HKs are an essential class of overlooked DBPs with a high contribution to drinking water cytotoxicity. Our study can help to explain the conflict that why regulated and priority DBPs (except HKs) just accounted for 16% of chlorinated drinking water cytotoxicity even enough they had much higher concentration and cytotoxicity than known aromatic DBPs.

An optimal method for diagnosing heart disease using combination of grasshopper evalutionary algorithm and support vector machines.

Due to the importance of accurate diagnosis and prompt treatment of this condition, the medical world is searching for a solution for its early detection and efficient treatment. Heart disease is one of the leading causes of death in modern society. With the development of computer science today, this issue can be resolved using computers. Data mining is one of the solutions for diagnosing this illness. One of the cutting-edge disciplines, data mining, can aid in better decision-making in many areas of medicine, including disease diagnosis and treatment. In order to improve diagnosis accuracy, a combination method using the evolutionary algorithms locust and support vector machine has been tested in this study. Use should be made of heart disease. Because of the hybrid nature of this approach, normalization is actually carried out in three steps: first, by using pre-processing operations to remove unknown and outlier data from the data set; second, by using the locust evolutionary algorithm to choose the best features from the available features; and third, by classifying the data set using a support vector machine. The accuracy criterion for the proposed method compared to Niobizin methods, neural networks, and J48 trees improved by 18 %, 30 %, and 24 %, respectively, after implementing it on the data set and comparing it with other algorithms used in the field of heart disease diagnosis.

The ideal model for determination the formation potential of priority DBPs during chlorination of free amino acids.

Amino acids (AAs) account for about 15-35% of dissolved organic nitrogen (DON), and are known as the important precursors of nitrogenous disinfection by-products (N-DBPs). Determining the formation potential (FP) of AAs to DBPs is used to reveal the key precursors of DBPs for further control, while the ideal method for N-DBPs FP of AAs during chlorination is not revealed. In this study, the ideal FP test models for five classes of priority DBPs during chlorination of four representative AAs (accounted for about 35% of total AAs) were analyzed. For haloaldehydes (HALs), haloketones (HKs), haloacetonitriles (HANs), haloacetamides (HAMs), and halonitromethanes (HNMs), their FPs during chlorination of four AAs were 0.1-13.0, 0.01-1.1, 0.1-104, not detectable (nd)-173, and nd-0.4 µg/mg, respectively. The FPs of priority DBPs had significant deviations between different FP test models and different tested AAs. For HALs, the model, whose chlorine dosage was determined by 15 × molar concentration of AAs [Cl (mM) = 15 × M](named: model II), was the ideal model. For HKs, model II was also the ideal FP test model for AAs with ≤3 carbons, while for AAs with 4 carbons, the model, whose chlorine dosage was determined by keeping the residual chlorine at 1 ± 0.2 mg/L after 24 h of reaction (named: model 4), was the ideal model. For HANs and HNMs, model 4 was the ideal FP test model for most of the studied AAs. The performance of HAMs during chlorination of amino acids was totally different from other P-DBPs, and model 3 was recommended to be the ideal model, in which chlorine dosage was determined by 3 × mass concentration of AAs [Cl (mg/L) = X × DOC]. This study is a reference that helps researchers select an ideal model for N-DBPs FP study of AAs.

Searching for Two-Neutrino and Neutrinoless Double Beta Decay of

^{134}Xe is a candidate isotope for neutrinoless double beta decay (0νßß) search. In addition, the two-neutrino case (2νßß) allowed by the standard model of particle physics has not yet been observed. With the 656-kg natural xenon in the fiducial volume of the PandaX-4T detector, which contains 10.4% of ^{134}Xe, and its initial 94.9-day exposure, we have established the most stringent constraints on 2νßß and 0νßß of ^{134}Xe half-lives, with limits of 2.8×10^{22} yr and 3.0×10^{23} yr at 90% confidence level, respectively. The 2νßß (0νßß) limit surpasses the previously reported best result by a factor of 32 (2.7), highlighting the potential of large monolithic natural xenon detectors for double beta decay searches.

Percutaneous cement-augmented short-segment pedicle screw fixation plus percutaneous vertebroplasty for stage III Kummell's disease without neurological symptoms: A case report.

INTRODUCTION: The incidence of stage III Kummell's disease without neurological symptoms is increasing in elderly patients with osteoporotic thoracolumbar fractures. However, the surgical method is still controversial in this condition. This report presented a case of Kummell's disease in which percutaneous bone cement-augmented short-segment pedicle screw fixation combined with percutaneous vertebroplasty was performed, providing a reference for the surgical approach. CASE PRESENTATION: The patient was a 72-year-old female who presented unexplained lower back pain accompanied with limited mobility for the past three months. Based on her medical history, physical examinations, and imaging studies, it was confirmed that she had Kummell's disease in stage III without neurological symptoms. We treated her with percutaneous bone cement-augmented short-segment pedicle screw fixation combined with percutaneous vertebroplasty on the symptomatic vertebrae. CLINICAL DISCUSSION: The majority of patients with stage III Kummell's disease have severe osteoporosis, which result in failure of the internal fixation and a series of other complications. Maintaining the stability of the internal fixation system is crucial, especially after screwing and subsequent locking. When augmented with bone cement, the grip and pull-out resistance of the percutaneous pedicle screws enhance greatly. Simultaneously, percutaneous vertebroplasty on the symptomatic vertebrae can immediately support the spine unit's stability mechanically and maintain the shape of the vertebrae after reduction. CONCLUSIONS: The percutaneous bone cement-augmented short-segment pedicle screw fixation combined with percutaneous vertebroplasty on the symptomatic vertebrae is an effective treatment for stage III Kummell's disease without neurological symptoms. It can effectively restore the vertebral height, correct the kyphotic deformities, improve spinal canal stenosis, and achieve satisfactory short-term clinical outcomes.

Insights into adsorbable organic halogen analysis: Two overlooked factors impacting water quality assessment.

Adsorbable organic halogen (AOX) represents the total amount of halogenated organics that can be adsorbed on activated carbon (AC) from samples. Measuring AOX is crucial for assessing water quality, and any erroneous estimation of AOX risks misleading decision-makers. This study demonstrated two overlooked factors that may introduce biases to AOX measurement. The first one relates to impurities in the gas transfer tubes of AOX combustion system and in the pressurized gas of AOX separation system, which resulted in significant fluctuations and high blank values (8.5-118.0 µg-Cl/L). The solutions of above issues are to warming up the combustor for several runs and replacing the pressurized air with argon gas in the separator, which could drop the blank AOX values to 9.1-10.0 µg-Cl/L. The second one involves coexisting chloride ion (Cl-) during AOX analysis, which interfered with AOX measurements (T. test, p < 0.05) even at low concentration levels (e.g., 10 mg/L Cl- in samples with 100 µg-Cl/L p-chlorophenol). Results show that AC captured 0.02-0.11 % of Cl-, resulting in 17.7-24.5 µg-Cl/L AOX responses in control samples containing 15-130 mg/L Cl- only. Furthermore, a significant mass imbalance of Cl- (3.58-8.39 %) during analysis process suggests a potential impact of residual Cl- on subsequent samples. By comparing synthetic and actual waters, samples with low dissolved organic carbon (DOC) were more susceptible to interference from Cl- on AOX measurement than those with high DOC. These findings underscore the pressing need to optimize existing AOX methods or develop alternative analytical methods to ensure accurate water quality assessment.

Insights into the inhibition of protospacer integration via direct interaction between Cas2 and AcrVA5.

Spacer acquisition step in CRISPR-Cas system involves the recognition and subsequent integration of protospacer by the Cas1-Cas2 complex in CRISPR-Cas systems. Here we report an anti-CRISPR protein, AcrVA5, and reveal the mechanisms by which it strongly inhibits protospacer integration. Our biochemical data shows that the integration by Cas1-Cas2 was abrogated in the presence of AcrVA5. AcrVA5 exhibits low binding affinity towards Cas2 and acetylates Cas2 at Lys55 on the binding interface of the Cas2 and AcrVA5 N-terminal peptide complex to inhibit the Cas2-mediated endonuclease activity. Moreover, a detailed structural comparison between our crystal structure and homolog structure shows that binding of AcrVA5 to Cas2 causes steric hindrance to the neighboring protospacer resulting in the partial disassembly of the Cas1-Cas2 and protospacer complex, as demonstrated by electrophoretic mobility shift assay. Our study focuses on this mechanism of spacer acquisition inhibition and provides insights into the biology of CRISPR-Cas systems.

Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults.

BACKGROUND: Sedentary behavior has been demonstrated to be a modifiable factor for several chronic diseases, while coffee consumption is believed to be beneficial for health. However, the joint associations of daily sitting time and coffee consumption with mortality remains poorly understood. This study aimed to evaluate the independent and joint associations of daily sitting time and coffee intakes with mortality from all-cause and cardiovascular disease (CVD) among US adults. METHODS: An analysis of a prospective cohort from the 2007-2018 National Health and Nutrition Examination Survey of US adults (n = 10,639). Data on mortality were compiled from interview and physical examination data until December 31, 2019. Daily sitting time was self-reported. Coffee beverages were from the 24-hour diet recall interview. The main outcomes of the study were all-cause and cardiovascular disease mortality. The adjusted hazard ratios [HRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. RESULTS: Among 10,639 participants in the study cohort, there were 945 deaths, 284 of whom died of CVD during the follow-up period of up to 13 years. Multivariable models showed that sitting more than 8 h/d was associated with higher risks of all-cause (HR, 1.46; 95% CI, 1.17-1.81) and CVD (HR, 1.79; 95% CI, 1.21-2.66) mortality, compared with those sitting for less than 4 h/d. People with the highest quartile of coffee consumption were observed for the reduced risks of both all-cause (HR, 0.67; 95% CI, 0.54-0.84) and CVD (HR, 0.46; 95% CI, 0.30-0.69) mortality compared with non-coffee consumers. Notably, joint analyses firstly showed that non-coffee drinkers who sat six hours or more per day were 1.58 (95% CI, 1.25-1.99) times more likely to die of all causes than coffee drinkers sitting for less than six hours per day, indicating that the association of sedentary with increased mortality was only observed among adults with no coffee consumption but not among those who had coffee intake. CONCLUSIONS: This study identified that sedentary behavior for more than 6 h/d accompanied with non-coffee consumption, were strongly associated with the increased risk of mortality from all-cause and CVD.

Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20.

Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays. Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14. Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression. Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children's families.

Reproductive toxicity of PFOA, PFOS and their substitutes: A review based on epidemiological and toxicological evidence.

Per- and polyfluoroalkyl substances (PFAS) have already drawn a lot of attention for their accumulation and reproductive toxicity in organisms. Perfluorooctanoic acid (PFOA) and perfluorooctanoic sulfonate (PFOS), two representative PFAS, are toxic to humans and animals. Due to their widespread use in environmental media with multiple toxicities, PFOA and PFOS have been banned in numerous countries, and many substitutes have been produced to meet market requirements. Unfortunately, most alternatives to PFOA and PFOS have proven to be cumulative and highly toxic. Of the reported multiple organ toxicities, reproductive toxicity deserves special attention. It has been confirmed through epidemiological studies that PFOS and PFOA are not only associated with reduced testosterone levels in humans, but also with an association with damage to the integrity of the blood testicular barrier. In addition, for women, PFOA and PFOS are correlated with abnormal sex hormone levels, and increase the risk of infertility and abnormal menstrual cycle. Nevertheless, there is controversial evidence on the epidemiological relationship that exists between PFOA and PFOS as well as sperm quality and reproductive hormones, while the evidence from animal studies is relatively consistent. Based on the published papers, the potential toxicity mechanisms for PFOA, PFOS and their substitutes were reviewed. For males, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Apoptosis and autophagy in spermatogenic cells; (2) Apoptosis and differentiation disorders of Leydig cells; (3) Oxidative stress in sperm and disturbance of Ca2+ channels in sperm membrane; (4) Degradation of delicate intercellular junctions between Sertoli cells; (5) Activation of brain nuclei and shift of hypothalamic metabolome. For females, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Damage to oocytes through oxidative stress; (2) Inhibition of corpus luteum function; (3) Inhibition of steroid hormone synthesis; (4) Damage to follicles by affecting gap junction intercellular communication (GJIC); (5) Inhibition of placental function. Besides, PFAS substitutes show similar reproductive toxicity with PFOA and PFOS, and are even more toxic to the placenta. Finally, based on the existing knowledge, future developments and direction of efforts in this field are suggested.